Senescent Cells Contribute to Brain Cancer

The SASP seems to discourage the immune system from attacking cancer.


Brain tumorBrain tumor

Combining results from human tumors and a mouse model, researchers publishing in Nature Communications have shown that senescent cells promote the growth of glioblastoma, a form of brain cancer.

Deadly, aggressive, and hard to treat

Glioblastoma is one of the most dangerous forms of cancer. Even surgery, radiotherapy, and chemotherapy do little against this invasive disease, and patients diagnosed with it survive for less than 15 months on average [1]. Glioblastoma suppresses the immune system’s efforts to remove it, and this paper shows how this seems to relate to the senescence-associated secretory phenotype (SASP).

Senescent cells have a double-edged relationship with cancer. While senescent cells normally do not divide, and cancer cells divide uncontrollably, there are more complicated biological effects in play. The SASP can promote immune clearance in some cases [2], but in other cases, it can directly promote tumor growth [3] and suppress the immune system in a way that encourages tumor growth [4]. One particular aspect of the SASP, interleukin 6 (IL-6), has been shown to promote cancer proliferation [5], and driving some cancers to senescence has shown short-term benefits but long-term harm, as the SASP drives their growth [6].

There are four distinct cell subpopulations in malignant glioblastoma tumors, relating to their phenotypic closeness to different types of brain cells, and the proportions of these subpopulations determine which of three general types it sits in [7]. Specifically, mesenchymal tumors, which contain cells similar to mesenchymal stem cells, are anti-inflammatory in a harmful way: they promote tumor-associated macrophages, which discourage immune clearance, and they are harder to treat with radiation therapies [8].


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Senescent cells encourage deadlier tumors

This study began with tumors taken from human beings. Staining for the common senescence marker SA-β-gal confirmed that senescent cells were present in these tumors, and additional analysis of p53 mutations found that these cells were themselves cancerous. There was no evidence that any specific molecular change was associated with the proportion of senescent cells.

The researchers then employed a mouse model of glioblastoma that is intended to accurately recapitulate the human condition. These mice had tumors that were very like their mesenchymal human counterparts, including in gene expression related to cellular senescence. There were senescent cells throughout these tumors, in both dying and proliferating regions, which comprised roughly 2% of the overall tumor size.

These mice were also modified to have senescent cells that die easily upon injection of a specific drug. Injecting this drug, which functioned as a senolytic in the mice, significantly improved their survival, as did injecting them with the well-known senolytic ABT-263.

As expected, genes related to the SASP were downregulated in the tumors of the treated mice. Critically, the gene expression of these tumors was also shown to shift away from the mesenchymal type and towards the less harmful types. The effects on genes related to tumor-associated macrophages were similarly beneficial.

NRF2, a common transcription factor that has antioxidant properties and is usually associated with preventing tumor growth, was found to promote tumor growth in this case. Knocking out NRF2 had similar effects as the senolytic treatments.


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These results come from cells and mice, so they don’t prove that senolytics will be effective against glioblastoma in human beings. However, the amount of supporting data, and the identification of the specific molecular causes and gene expression profiles in the presence of the SASP, makes it clear that targeting senescent cells is worth exploring as a strategy to be used alongside existing therapies against glioblastoma.

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[1] Stupp, R., Mason, W. P., Van Den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., … & Mirimanoff, R. O. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England journal of medicine, 352(10), 987-996.

[2] Kang, T. W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., … & Gereke, M. (2011). 632 Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, 633 Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S and Zender L. 634 Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature, 635(479), 547-551.

[3] Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., … & Ohtani, N. (2013). Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature, 499(7456), 97-101.

[4] Ruhland, M. K., Loza, A. J., Capietto, A. H., Luo, X., Knolhoff, B. L., Flanagan, K. C., … & Stewart, S. A. (2016). Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nature communications, 7(1), 11762.


[5] Wang, H., Lathia, J. D., Wu, Q., Wang, J., Li, Z., Heddleston, J. M., … & Rich, J. N. (2009). Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem cells, 27(10), 2393-2404.

[6] Balakrishnan, I., Danis, E., Pierce, A., Madhavan, K., Wang, D., Dahl, N., … & Venkataraman, S. (2020). Senescence induced by BMI1 inhibition is a therapeutic vulnerability in H3K27M-mutant DIPG. Cell reports, 33(3), 108286.

[7] Wang, L., Babikir, H., Müller, S., Yagnik, G., Shamardani, K., Catalan, F., … & Diaz, A. A. (2019). The Phenotypes of Proliferating Glioblastoma Cells Reside on a Single Axis of VariationA Draft Single-cell Atlas of Human Glioma. Cancer discovery, 9(12), 1708-1719.

[8] Bhat, K. P., Balasubramaniyan, V., Vaillant, B., Ezhilarasan, R., Hummelink, K., Hollingsworth, F., … & Aldape, K. (2013). Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer cell, 24(3), 331-346.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.